Lennox-Gastaut Syndrome (LGS) is a severe pediatric epilepsy disorder associated with various types of seizures and cognitive dysfunction that persist into adulthood. As a result, LGS patients suffer from varying degrees of learning disabilities, psychiatric disorders, and behavioral disturbances that can drastically affect their social integration. Diagnosis and ensuing management of LGS is challenging, relying mostly on the expertise of the treating physician to interpret an intricate amalgamation of clinical and EEG abnormalities. Although limited clinical trials suggest that a small subset of available anti-epileptic drugs such as lamotrigine, valproic acid, topiramate, felbamate, and clobazam may be used to manage the multiple seizure types associated with LGS, their efficacy is often inadequate and perilous adverse effects (AEs) may occur. The relatively new drug rufinamide, a compound with orphan drug status in the USA (2004) and marketing authorization in Europe (2007), displays a broad spectrum of anti-epileptic activity and clinical trials have demonstrated long-term beneficial effects and good tolerability when used as adjunctive therapy in children and adult LGS patients.
Anomalous hNav1.1 behavior (molgen.vib-ua.be/scn1amutations/) have been implicated in Lennox-Gastaut Syndrome as well as partial or refractory focal seizures.
Given their unique role in electrical signaling and subsequent implications in various epilepsy disorders, voltage-gated sodium (Nav) channels within the central nervous system (CNS) are influenced by anti-epileptic drugs (AEDs). Of the nine Nav channel isoforms (Nav1.1-Nav1.9) identified in humans, four are expressed predominantly in the CNS (Nav1.1 (SCN1A), Nav1.2 (SCN2A), Nav1.3 (SCN3A), and Nav1.6 (SCN8A)). Supporting their physiological importance, mutations in Nav1.1 (more than 1200), Nav1.2, and Nav1.6 have been linked to various epilepsy phenotypes whereas Nav1.3 is believed to also be involved in nociception after channel upregulation due to spinal cord injury.
As such, there still exists an unmet need to understand the mechanism of action of voltage-gated sodium (Nav) in various neurological diseases and discovery of better and more efficacious drugs to treat LGS and other epilepsy related diseases.